Oct-4

Last updated
POU5F1
OCT4 prot.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases POU5F1 , OCT3, OCT4, OTF-3, OTF3, OTF4, Oct-3, Oct-4, POU class 5 homeobox 1, Oct3/4
External IDs OMIM: 164177 MGI: 101893 HomoloGene: 8422 GeneCards: POU5F1
Orthologs
SpeciesHumanMouse
Entrez

5460

18999

Ensembl

ENSMUSG00000024406

UniProt

Q01860

P20263

RefSeq (mRNA)

NM_203289
NM_001173531
NM_001285986
NM_001285987
NM_002701

Contents

NM_001252452
NM_013633

RefSeq (protein)

NP_001239381
NP_038661

Location (UCSC) Chr 6: 31.16 – 31.18 Mb Chr 17: 35.82 – 35.82 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Oct-4 (octamer-binding transcription factor 4), also known as POU5F1 (POU domain, class 5, transcription factor 1), is a protein that in humans is encoded by the POU5F1 gene. [5] Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. [6] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells. [7]

Octamer-binding transcription factor 4, OCT-4, is a transcription factor protein that is encoded by the POU5F1 gene and is part of the POU (Pit-Oct-Unc) family. [8] OCT-4 consists of an octamer motif, a particular DNA sequence of AGTCAAAT that binds to their target genes and activates or deactivates certain expressions. These gene expressions then lead to phenotypic changes in stem cell differentiation during the development of a mammalian embryo. [9] It plays a vital role in determining the fates of both inner mass cells and embryonic stem cells and has the ability to maintain pluripotency throughout embryonic development. [10] Recently, it has been noted that OCT-4 not only maintains pluripotency in embryonic cells but also has the ability to regulate cancer cell proliferation and can be found in various cancers such as pancreatic, lung, liver and testicular germ cell tumors in adult germ cells. [11] Another defect this gene can have is dysplastic growth in epithelial tissues which are caused by a lack of OCT-4 within the epithelial cells. [12]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte and remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors. [13] Gene knockdown of Oct-4 promotes differentiation, demonstrating a role for these factors in human embryonic stem cell self-renewal. [14] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together. [15]

Mouse embryos that are Oct-4 deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency, and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs

Orthologs of Oct-4 in humans and other species include:

SpeciesEntrez GeneIDChromosomeLocationRefSeq (mRNA)RefSeq (protein)
Mus musculus (mouse) 18999 17,17 B1; 17 19.23 cMNC_000083.4, 35114104..35118822 (Plus Strand) NM_013633.1 NP_038661.1
Homo sapiens (human) 5460 6, 6p21.31NC_000006.10, 31246432-31240107 (Minus Strand) NM_002701.3 NP_002692.2 (full length isoform)
NP_002692.1 (N-terminal truncated isoform)
Rattus norvegicus (rat) 294562 20NW_001084776, 650467-655015 (Minus strand) NM_001009178 NP_001009178
Danio rerio (zebrafish) 303333 21NC_007127.1, 27995548-28000317 (Minus strand) NM_131112 NP_571187

Structure

Oct-4 contains the following protein domains:

DomainDescriptionLength (AA)
POU domain Found in Pit-Oct-Unc transcription factors75
Homeodomain DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homodimers and/or heterodimers in a sequence-specific manner.59

Implications in disease

Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation. [16]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem cells to determine requirements for Oct-4 in the maintenance of developmental potency. [7] Although transcriptional determination has often been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. An increase in expression of less than 2-fold causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down-regulation induces divergent developmental programs. Changes to Oct-4 levels do not independently promote differentiation, but are also controlled by levels of Sox2. A decrease in Sox2 accompanies increased levels of Oct-4 to promote a mesendodermal fate, with Oct-4 actively inhibiting ectodermal differentiation. Repressed Oct-4 levels that lead to ectodermal differentiation are accompanied by an increase in Sox2, which effectively inhibits mesendodermal differentiation. [17] Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.

The transcription factors Oct-4, Sox2, and Nanog are part of a complex regulatory network, with Oct-4 and Sox2 being capable of directly regulating Nanog by binding to its promoter, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, embryonic stem cell lines [18] (which are cell lines derived from the inner cell mass), and induced pluripotent stem cells. [15] While differential up- and down-regulation of Oct-4 and Sox2 has been shown to promote differentiation, down-regulation of Nanog must occur for differentiation to proceed. [17]

Role in reprogramming

Oct-4 is one of the transcription factors that is used to create induced pluripotent stem cells (iPSCs), together with Sox2, Klf4, and often c-Myc (OSKM) in mice, [19] [20] [21] demonstrating its capacity to induce an embryonic stem-cell-like state. These factors are often referred to as "Yamanaka reprogramming factors". This reprogramming effect has also been seen with the Thomson reprogramming factors, reverting human fibroblast cells to iPSCs via Oct-4, along with Sox2, Nanog, and Lin28. The use of Thomson reprogramming factors avoids the need to overexpress c-Myc, an oncogene. [22] It was later determined that only two of these four factors, namely Oct4 and Klf4, are sufficient to reprogram mouse adult neural stem cells. [23] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation. [24] Moreover, while Sox2, Klf4, and cMyc could be replaced by their respective family members, Oct4's closer relatives, Oct1 and Oct6, fail to induce pluripotency, thus demonstrating the exclusiveness of Oct4 among POU transcription factors. [25] However, later it was shown that Oct4 could be completely omitted from the Yamanaka cocktail, and the remaining three factors, Sox2, Klf4, and cMyc (SKM) could generate mouse iPSCs with dramatically enhanced developmental potential. [26] This suggests that Oct4 increases the efficiency of reprogramming, but decreases the quality of resulting iPSCs.

In embryonic stem cells

In adult stem cells

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.). [31] Other scientists have produced evidence to the contrary, [32] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal, [33] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression. [34] Oct-4 has also been implicated as a marker of cancer stem cells. [35] [36]

See also

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

Transdifferentiation, also known as lineage reprogramming, is the process in which one mature somatic cell is transformed into another mature somatic cell without undergoing an intermediate pluripotent state or progenitor cell type. It is a type of metaplasia, which includes all cell fate switches, including the interconversion of stem cells. Current uses of transdifferentiation include disease modeling and drug discovery and in the future may include gene therapy and regenerative medicine. The term 'transdifferentiation' was originally coined by Selman and Kafatos in 1974 to describe a change in cell properties as cuticle producing cells became salt-secreting cells in silk moths undergoing metamorphosis.

<span class="mw-page-title-main">Cellular differentiation</span> Developmental biology

Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. However, metabolic composition does get altered quite dramatically where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.

<span class="mw-page-title-main">Homeobox protein NANOG</span> Mammalian protein found in humans

Homeobox protein NANOG(hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the NANOG gene. Several types of cancer are associated with NANOG.

In biology, reprogramming refers to erasure and remodeling of epigenetic marks, such as DNA methylation, during mammalian development or in cell culture. Such control is also often associated with alternative covalent modifications of histones.

SOX genes encode a family of transcription factors that bind to the minor groove in DNA, and belong to a super-family of genes characterized by a homologous sequence called the HMG-box. This HMG box is a DNA binding domain that is highly conserved throughout eukaryotic species. Homologues have been identified in insects, nematodes, amphibians, reptiles, birds and a range of mammals. However, HMG boxes can be very diverse in nature, with only a few amino acids being conserved between species.

<span class="mw-page-title-main">Inner cell mass</span> Early embryonic mass that gives rise to the fetus

The inner cell mass (ICM) or embryoblast is a structure in the early development of an embryo. It is the mass of cells inside the blastocyst that will eventually give rise to the definitive structures of the fetus. The inner cell mass forms in the earliest stages of embryonic development, before implantation into the endometrium of the uterus. The ICM is entirely surrounded by the single layer of trophoblast cells of the trophectoderm.

<span class="mw-page-title-main">Induced pluripotent stem cell</span> Pluripotent stem cell generated directly from a somatic cell

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. The iPSC technology was pioneered by Shinya Yamanaka and Kazutoshi Takahashi in Kyoto, Japan, who together showed in 2006 that the introduction of four specific genes, collectively known as Yamanaka factors, encoding transcription factors could convert somatic cells into pluripotent stem cells. Shinya Yamanaka was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."

<span class="mw-page-title-main">SOX2</span> Transcription factor gene of the SOX family

SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.

<span class="mw-page-title-main">Shinya Yamanaka</span> Japanese stem cell researcher

Shinya Yamanaka is a Japanese stem cell researcher and a Nobel Prize laureate. He is a professor and the director emeritus of Center for iPS Cell Research and Application, Kyoto University; as a senior investigator at the UCSF-affiliated Gladstone Institutes in San Francisco, California; and as a professor of anatomy at University of California, San Francisco (UCSF). Yamanaka is also a past president of the International Society for Stem Cell Research (ISSCR).

<span class="mw-page-title-main">SALL4</span> Protein-coding gene in the species Homo sapiens

Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.

<span class="mw-page-title-main">Rex1</span> Known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells

Rex1 (Zfp-42) is a known marker of pluripotency, and is usually found in undifferentiated embryonic stem cells. In addition to being a marker for pluripotency, its regulation is also critical in maintaining a pluripotent state. As the cells begin to differentiate, Rex1 is severely and abruptly downregulated.

<span class="mw-page-title-main">FOXD3</span> Protein-coding gene in the species Homo sapiens

Forkhead box D3 also known as FOXD3 is a forkhead protein that in humans is encoded by the FOXD3 gene.

<span class="mw-page-title-main">Cell potency</span> Ability of a cell to differentiate into other cell types

Cell potency is a cell's ability to differentiate into other cell types. The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell, which like a continuum, begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency, and finally unipotency.

Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body. Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromatin structure as well as specific gene transcription programs. Epigenetics has been used to refer to changes in gene expression, which are heritable through modifications not affecting the DNA sequence.

<span class="mw-page-title-main">UTF1</span> Protein-coding gene in the species Homo sapiens

Undifferentiated embryonic cell transcription factor 1 is a protein in humans that is encoded by the UTF1 gene. UTF1, first reported in 1998, is expressed in pluripotent cells including embryonic stem cells and embryonic carcinoma cells. Its expression is rapidly reduced upon differentiation. UTF1 protein is localized to the cell nucleus, where it functions to regulate the pluripotent chromatin state and buffer mRNA levels by promoting degradation of mRNA.

Directed differentiation is a bioengineering methodology at the interface of stem cell biology, developmental biology and tissue engineering. It is essentially harnessing the potential of stem cells by constraining their differentiation in vitro toward a specific cell type or tissue of interest. Stem cells are by definition pluripotent, able to differentiate into several cell types such as neurons, cardiomyocytes, hepatocytes, etc. Efficient directed differentiation requires a detailed understanding of the lineage and cell fate decision, often provided by developmental biology.

After the blastocyst stage, once an embryo implanted in endometrium, the inner cell mass (ICM) of a fertilized embryo segregates into two layers: hypoblast and epiblast. The epiblast cells are the functional progenitors of soma and germ cells which later differentiate into three layers: definitive endoderm, mesoderm and ectoderm. Stem cells derived from epiblast are pluripotent. These cells are called epiblast-derived stem cells (EpiSCs) and have several different cellular and molecular characteristics with Embryonic Stem Cells (ESCs). Pluripotency in EpiSCs is essentially different from that of embryonic stem cells. The pluripotency of EpiSCs is primed pluripotency: primed to differentiate into specific cell lineages. Naïve pluripotent stem cells and primed pluripotent stem cells not only sustain the ability to self-renew but also maintain the capacity to differentiate. Since the cell status is primed to differentiate in EpiSCs, however, one copy of the X chromosome in XX cells in EpiSCs is silenced (XaXi). EpiSCs is unable to colonize and is not available to be used to produce chimeras. Conversely, XX cells in ESCs are both active and can produce chimera when inserted into a blastocyst. Both ESC and EpiSC induce teratoma when injected in the test animals which proves pluripotency. EpiSC display several distinctive characteristics distinct from ESCs. The cellular status of human ESCs (hESCs) is similar to primed state mouse stem cells rather than naïve state.

<span class="mw-page-title-main">F-box protein 15</span>

F-box protein 15 also known as Fbx15 is a protein that in humans is encoded by the FBXO15 gene.

<span class="mw-page-title-main">David Suter (biologist)</span> David Suter, Swiss cell biologist

David Suter is a Swiss physician and molecular and cell biologist. His research focuses on quantitative approaches to study gene expression and developmental cell fate decisions. He is currently a professor at EPFL, where he heads the Suter Lab at the Institute of Bioengineering of the School of Life Sciences.

References

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  31. ↑ For example:
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Further reading

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